July 13, :30 p.m. (ET)

Transcription

1 Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury Webinar Series Prevalence of and Screening for Neuroendocrine Dysfunction Post Mild Traumatic Brain Injury July 13, :30 p.m. (ET) Operator: Good afternoon and welcome to the TBI webinar. For the duration of today's conference, all participants' lines are on a listen-only mode. It is my pleasure to introduce Mr. Scott Blair. Thank you. Sir, you may begin. Good day and thank you for joining us today for the DCoE traumatic brain injury July webinar, prevalence of excuse me, Prevalence of and Screening for Neuroendocrine Dysfunction Post Mild Traumatic Brain Injury. My name is Scott Blair. I'm the director the Pituitary Injury Foundation. I'll be your moderator for today's webinar. Now, today's presentation is available for download from the files pod and of the archive in the online education section of the DVBIC website. Before we begin, let us review some webinar details. If you experience technical difficulties, please visit dcoe.mil/webinars to access any troubleshooting tips. Please feel free to identify yourself to other attendees via the chat box but refrain from marketing your organization for a product. All who wish to obtain continuing education credit or certificate of attendance and who meet eligibility requirements must complete the online CE evaluation. After the webinar, please visit dcoe.cds.pesgce.com to complete the online CE evaluation and download or print you CE certificate or certificate of attendance. The evaluation will be open through Thursday, July 27th Throughout the webinar, you're welcome to submit technical or content related questions via the Q&A pod located on the screen. All questions will be anonymous but please do not submit technical or content related questions via the chat pod. I will now move on to today's webinar. Prevalence and screening for neuroendocrine dysfunction post mild traumatic brain injury. Studies of civilian brain injuries from all causes have found a 25% to 50% prevalence of chronic endocrine disorders due to damaged or disruption of neural and vascular regulation of the pituitary gland. Common symptoms of neuroendocrine dysfunction include cognitive deficits, sleep disorders, sexual dysfunction, fatigue, depression, social isolation, deleterious changes and body composition and reduced quality of life. Mild traumatic brain injury or TBI or concussion is the single most frequent injury sustained by US combat troops deployed to Iraq or Afghanistan. The injuries are very often caused by blast waves from improvised explosive devices. The presenter will discuss a study designed to, one, determine the prevalence of chronic neuroendocrine dysfunction resulting from explosive blast-related

2 concussions in veterans deployed in Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn. Number two, you identify the frequency or current individual endocrine disorders in these veterans. Number three, administer neuropsychological test and questionnaires proving the severity of behavioral symptoms. Number four, attempt to relate specific symptoms to individual endocrine abnormalities. Five, offer referral to an endocrinologist to veterans who screened positive for neuroendocrine dysfunction. At the conclusion of this presentation, participants will be able to describe the basic anatomy and physiology of the human pituitary gland including the characteristics that make it vulnerable to damage from traumatic brain injury or TBI. They'll be able to identify the defining criteria established by the American Congress of Rehabilitation Medicine where the diagnosis of concussion/mild TBI, which will be abbreviated in this talk as MTBI. They'll be able to articulate a typical natural history or time course of the development and/or resolution of neuroendocrine disorders resulting from mild TBI. Differentiate the injury mechanisms involved in blast-related concussion from those of concussion due to impact. They'll also name the two most prevalent chronic neuroendocrine disorders associated with an MTBI. Lastly, list five neurobehavioral symptoms of neuroendocrine dysfunction or NED that may result from an explosive blastrelated concussion. I'd like to introduce Dr. Wilkinson. Dr. Wilkinson is a research physiologist at the VA Puget Sound Healthcare System. He is also a research professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington and is the neuroendocrine researcher of chronic pituitary dysfunction after blast-related MTBI. His previous research emphasized hypothalamicpituitary-adrenal physiology and behavior. Dr. Wilkinson has over 110 peerreviewed scientific publications and received his PhD in Psychology at the University of California, Santa Barbara. Please welcome Dr. Wilkinson. Dr. Wilkinson: Hello and thank you for joining the program. Mr. Blair has presented much of what I was going to say in my opening statement. I will just run through a brief summary of what I'm going to say. The first, some background information then I'll move to the anatomy of the pituitary gland, then the major symptoms of each pituitary hormone deficiency, and approaches to screening for NED. Then I'll end by presenting our data from the study that Mr. Blair mentioned, showing some evidence of some of the behavioral and cognitive problems that result from NED. I have no relevant financial relationships to disclose. This thing shows the number of active duty service members anywhere US forces are located with the first time TBI diagnosis since Note that these are first time diagnosis so that subsequent TBIs for a given individual are not included. Unreported or undiagnosed TBIs are not included. Therefore, this chart significantly under estimates the total number of TBIs sustained by active duty service members. 2

3 Over 82% of the TBIs experienced by members of the armed forces trying to get the arrow here, all right. Over 82% were classified as MTBI, a term that the DOD and VA used interchangeably with concussion. Considering that the likelihood of a concussion being reported is much lower than that of a more severe injury. The incidence of MTBIs is almost certainly even more markedly under estimated. What is mild TBI? The most widely accepted definition is that from the American Congress of Rehabilitation Medicine. It's a traumatically induced disruption of brain function resulting in any one or more of the following: loss of consciousness, posttraumatic amnesia, alteration of mental state, focal neurologic deficits or a Glasgow coma scale score of 13 to 15. The GSS/GCS is accumulative score of visual, verbal and motor responses that serves as an indicator of the initial conscious date after the trauma. It's limited to immediate evaluation by a medical personnel at the time of the injury. I'm going to focus not only on MTBI but specifically on blast-related MTBI. Blastrelated concussion is the single most frequently reported injury of combat in Iraq and Afghanistan. During the years 2005 to 2009, nearly three quarters of all combat injuries were due to explosions. 10% to 20% of returnees from deployment in Iraq or Afghanistan report at least one concussion. The injury mechanisms of blast MTBI are extremely complex. Blast pressure is transmitted both to the skull and via blood vessels. Blast waves produce rapid acceleration, deceleration and rotation of the brain within the skull. The force of the blast often results in secondary impact of the head with the ground or surrounding objects in close spaces, the way this may reflect and impinge from multiple directions causing considerable amplification of the force. Blast waves are accompanied by intense heat, fragment impact, emitted gases and electromagnetic waves. The transfer of the shock waves energy to and through the torso can lead to hypoxia caused by alveolar damage in the lungs and the sudden surges in blood flow that can disrupt microvasculature throughout the body. I'll move here to background information about the pituitary gland. It's located at the base of the brain, below the hypothalamus and it's about the size of garbanzo bean, shown here in blue on the slide. It's often described as the master gland because its secretory products regulate the function of the other endocrine glands. Pituitary is composed of two lobes, the anterior and the posterior. The anterior pituitary is on the left in the slide and the posterior on the right. The two major hormones secreted by the posterior pituitary are oxytocin and vasopressin, also known antidiuretic hormone or ADH. Oxytocin plays a role in activation of the milk ejection reflex during lactation and contraction of uterine muscle during parturition. Oxytocin is also been implicated in about wide variety of physiological systems and there are ongoing studies of effects in reducing food intake and ameliorating both pain and depression. Vasopressin functions primarily as regulator of salt and water balance by 3

4 stimulating the resorption of water by the kidneys. It also aids in regulating blood pressure by modulating vasoconstriction, that's been in vasopressin. Dr. Wilkinson: There is increasing evidence to support a wider role for both peptides in the neuroregulation of complex behavior. However, it's the anterior pituitary and its hormonal secretions would be the major focus of the presentation and of the screening process for NED. There are six anterior pituitary major hormones secreted by the anterior pituitary and they're indicated by the arrows on the left of this figure. The next arrow is to the right represent the target organs regulated by each hormone. The arrows on the far right indicate the hormones produced by the target organs in response to the pituitary hormones. Growth hormone acts on multiple organs and tissues including the brain to regulate growth and metabolism and stimulates hepatic production of insulin-like growth factor I or IGF-I, which also plays a metabolic role. The two gonadotropins, luteinizing hormone and follicle-stimulating hormone regulate the menstrual cycle as well as the production of menstrual cycle and reproductive function, as well as the production of estradiol and progesterone in women and testosterone in men. Prolactin promotes milk ejection of milk production during lactation excuse me, and affects reproductive and sexual function in both genders and has many other functions in multiple systems. ACTH or adrenocorticotropin and TSH or thyroid-stimulating hormone regulate the function of the adrenal cortex and the thyroid respectively. The adrenal cortex produces the stress hormone, cortisol, and the thyroid secretes thyroxine and triiodothyronine. Let's now look at the aspects of the anatomy that make the pituitary vulnerable to TBI. It's tethered to the hypothalamus by a narrow stalk, two to three millimeters in diameter in a little trouble with the arrow out here, sorry, which is the glands primary vascular and neural supply. This is shown more clearly on the earlier slide, go back to that. You can see clearly the neural input to the posterior pituitary here and the vascular input from the hypothalamus to the anterior pituitary. I'm going to leave this arrow on the slide. I hope it isn't too distracting. It's easier this way. The gland itself is almost completely encased in a bony pocket in the sphenoid called the sella turcica or Turkish saddle because of its shape. The pituitaries confined immobility makes it susceptible to compression by brain movement or edema. That is also vulnerable to vascular pressure surges and hypoxia due to the blast wave effects on the torso and by damage to the hypothalamus and other brain regions that are involved in its regulation. This slide recapitulates the information illustrated on the previous slide. The pituitary is subject to compression from impact or edema. The stalk is highly vulnerable to brain movement, damage to upstream neural processes and transmission of pressure waves to the vasculature can also cause pituitary dysfunction. This slide and the following slide were kindly provided by Mr. Scott Blair, today's moderator. The slide illustrates the brain movement within the skull 4

5 caused by impact or a sudden traumatic change in head movement or whiplash or by a blast over pressure wave. This slide illustrates the distortion and pressure applied to the pituitary stalk by brain movement. The stretching of the stalk between the moving brain and the rigidly confined gland can cause micro tears in axons and blood vessels. The first case of TBI-induced NED, neuroendocrine dysfunction was reported in 1918 but the condition was considered rare for many years. On the publications in the 1960s, on pituitary necropsy in 20% to 30% of daily head injured patients, the first perspectives that it wasn't published until 2000, this is a new area. Since then, over 40 studies of chronic TBI-induced NED has appeared, more than half of which have reported a prevalence of chronic NED after TBI of 25% to 50%. What are the chronic consequences for psychological health of TBI-induced NED? Among them are cognitive deficits, sleep difficulties, mood disorders, fatigue and diminished quality of life. The symptoms overlap considerably with those of post-concussive syndrome in PTSD. However, if in a given case, some or all of these symptoms are due to NED. They can often be treated successfully with hormone replacement. On the other hand, failure to screen for NED may result in inappropriate and ineffective treatment of these symptoms. These are some of the symptoms common to both PTSD and posttraumatic NED. The temporal pattern of neuroendocrine disorders that occur because of a brain injury generally consists of two phases. In the acute phase, the violent stress of the trauma causes multiple endocrine abnormalities immediately after the incident. During the following weeks and months, some abnormalities resolve whereas a smaller proportion of new dysfunctions may emerge over time up to months afterwards. After one year, posttraumatic hypopituitarism or NED is considered essentially permanent. A relative frequency of individual hormone deficiencies differs substantially between the acute and the chronic phases. The most common disorder occurring during the acute phase is central diabetes insipidus, a mark deficiency of vasopressin or antidiuretic hormone. This deficiency results in water loss through excessive production of very dilute urines. The second most frequent disorder during the acute phase is secondary adrenal insufficiency, which is decrease secretion of the stress hormone, cortisol, due to inadequate pituitary production of ACTH. Hypothyroidism caused by deficiency affects secretion as the most prevalent type of acute post TBI NED. During the chronic phase of NED, growth hormone deficient excuse me, deficiency, GHD, is by far the most prevalent disorder. Next in frequency and chronic NED is LH and/or FSH deficiency, luteinizing hormone or folliclestimulating hormone leading to amenorrhea in women and hypogonadism characterized by infertility and social dysfunction in both men and women. In third place in terms of chronic endocrine disorders is adrenal insufficiency. In the next few slides describe the most common symptoms or deficiencies in each of the pituitary hormones. Growth hormone deficiency has been the most frequently observed hormone abnormality and virtually every study of chronic posttraumatic NED. Growth 5

6 hormone deficiency is become recognized significant clinical entity with serious consequences including negative effects on mood, sleep, fatigue, learning and memory, and other dimensions of quality of life. It also has deleterious effects on metabolism, body composition and increased cardiovascular mortality. Hypogonadism is second most prevalent hormonal disorders seen in posttraumatic NED. It is due to deficiency of FSH and/or LH. Dr. Wilkinson: There are the two gonadotropic hormones overlapping and synergistic functions in men, LH is associated primarily with testosterone synthesis and secretion and FSH was spermatogenesis. In women, an acute rise in LH triggers ovulation and development of the corpus luteum whereas FSH stimulates growth and development of ovarian follicles. Deficiencies of these hormones in both genders can cause multiple problems not directly associated with sexual and reproductive function including depression, fatigue, sleep disorders and osteoporosis. Cortisol is secreted from the adrenal cortex in response to environmental, physical and psychological stresses as well as homeostatic imbalances such as hypoglycemia. Cortisol functions to mobilize glucose by increasing glucogenesis and decreasing peripheral utilization. These are some of the symptoms of cortisol deficiency. Central hypothyroidism is due to insufficient secretion of TSH results in the general suppression of metabolism that affects multiple systems. You may have noticed the recurrence of the themes of fatigue, depression, cognitive deficits, sexual dysfunction and metabolic abnormalities that appear in the list of symptoms of apparent levels, each of the hormones. This constellation of symptoms is frequently observed in individuals with TBI-induced NED. Prolactin is unique among the anterior pituitary hormones and that it is under primarily inhibitory regulation by the brain. Its secretion is suppressed by dopamine. In the absence of dopaminergic input, prolactin secretion increases markedly. Hyperprolactinemia is frequently caused by benign pituitary prolactinomas or by inhibition of hypothalamic secretion of dopamine by antipsychotic medications. All typical antipsychotic medications are potent antagonist of dopamine excuse me, and reverse its inhibition of prolactin secretion. Some atypically antipsychotic such as Risperidone and amisulpride have similar actions. Hyperprolactinemia may result in inappropriate milk secretion or amenorrhea in women and sexual productive dysfunction in both men and women. Hypoprolactinemia is extremely rare in the absence of other pituitary hormone deficits. It can occur as a consequence of TBI. It's most prominent effect is the year of post-delivery milk production. Like the excessive prolactin secretion of hypoprolactinemia, a deficiency of prolactin may also lead to sexual dysfunction. This ends my discussion of the symptoms of the variant anterior pituitary hormone secretion. I'll now move on to cover posterior pituitary hormone symptoms of abnormalities and excessive vasopressin levels can lead to significant health problems. As mentioned earlier, various low circulating concentrations of vasopressin can lead to potentially life threatening high volumes of water loss due to failure 6

7 resorption by the kidneys together with plasma hyperosmolality and extreme thirst. At the other end of the concentration spectrum, the syndrome of inappropriate antidiuretic hormone secretion leads to water retention, plasma hypoosmolality and low sodium levels. In extreme cases, it can lead to confusion, disorientation and generalized muscle weakness. Recently, suggestive evidence is accumulated for the association of high levels of vasopressin with personality disorder, depression, obsessive compulsive disorder, schizophrenia and PTSD. The cause of effects have not been demonstrated. In some respects, the effects of oxytocin are mood and behavior appear to oppose the effects of excessive vasopressin. Oxytocin, which is fundamental to the milk ejection reflex during nursing is an important mediator of mother and child bonding. This function and evidence for its salutatory role in multiple aspects of social behavior and social interaction have led to the elevation of the stature of oxytocin as the love hormone in a popular press. There are suggestive evidence that oxytocin deficiencies maybe associated with depression particularly in women. Mental disorders characterized by severe social disturbances such as autism. We've briefly discussed the induction of multiple neurobehavioral and physiological symptoms in chronic NED but under what circumstances should NED be screened for in relation to MTBI. This slide shows the recommendations of Defense and Veterans Brain Injury Center, DVBIC, and the Defense Center is of excellence for psychological health and traumatic brain injury for determining when NED screening is appropriate after an MTBI. The conditions are, the presence of suggestive persistent MTBI symptoms that did not resolve within three months of injury, emergence of new symptoms up to three years from the concussion, and the presence of symptoms that reliable that are behavioral and cognitive disorders. Here are DVBIC and DCoE recommendations for the laboratory screening or hormones when suggested by indications of NED. The hormones listed for screening include almost all of the anterior pituitary and target organ hormones that I've discussed here. Vasopressin and oxytocin levels are generally not screened in the absence of specific symptoms. Here are some more specific details about what factors to attend to in screening for anterior pituitary hormone deficiencies. As described in the slide, in general, measurement of the circulating concentrations of the target organ hormones rather than the pituitary hormones themselves. It provides the most useful diagnostic information. Defining characteristics of adrenal insufficiency, hypothyroidism and hypogonadism, both men and women are the levels of the target organs, cortisol, thyroxin, and estradiol or testosterone respectively. This is because in addition to infiltrating the hypothalamus and other brain areas, pituitary hormone secretion is regulated by negative feedback inhibition from the target organ hormones. Feedback signaling a deficient levels of target organ hormones activates the hypothalamus to stimulate increase pituitary hormone secretion to the extent that those levels maybe within normal range but still insufficient to sustain optimal function of the 7

8 Dr. Wilkinson: I've mentioned the growth hormone deficiency is the most prevalent form of chronic NED observed after a concussion. Unfortunately, it's also the most difficult and time and labor intensive to screen for. Growth hormone secretion occurs almost entirely during the night. Measurement of a single daytime sample will yield either extremely low or unmeasurable concentrations or might coincide with one of the small irregular spikes that occur during the daytime. In either case, the measurement will not provide any evidence of daily growth hormone secretion. One option for making a preliminary diagnosis of GHD is to measure the levels of IGF-I that's secreted from the liver in response to growth hormones. Very low levels of IGF-I are strongly predictive to GHD. The GHD may still be present even if IGF-I concentrations are moderate or high. The second and only reliable measure of pituitary capacity to produce growth hormone is by provocative testing. The two most frequently used tests are the insulin tolerance test and the glucagon stimulation test. In an individual with a normally functioning pituitary, either an insulin or glucagon administration will provoke a significant increase in circulating growth hormones as well as ACTH and cortisol. The absence of a growth hormone response indicates growth hormone deficiency. The IGT is considered the gold standard for identifying growth hormone deficiency. It requires close medical supervision because of the hypoglycemia and it's contraindicated in case of [head injury 00:30:55]. The glucagon stimulation test is better tolerated and safer but it's considered somewhat less reliable by some endocrinologist. This is a portion of a DVBIC, DCoE reference card containing an algorithm for clinical decision making based on results of hormone screening. This reference card is one of three items that are available. Mr. Blair will discuss them at the end of the talk but these are sources of information for diagnosing and screening for NED. I'd now like to switch from general information about NED to the presentation of a study we're currently conducting. We're enrolling veterans who are deployed as part of OEF, OIF or OND. We're investigating the prevalence of NED in these veterans and the effects of NED on neurobehavioral function. Despite the high frequency of NED that's been found in civilian studies and the fact that blast-induced TBI is the most common single injury of modern warfare, no studies of the prevalence of hypopituitarism after blast concussion had been published when we started this work. Our primary goal is to determine whether blast-induced concussions resolve in rates of pituitary hormone deficiencies comparable to those found in previous studies of civilian TBI-induced NED and to determine the frequency of individual hormone deficiencies. The study two groups of male US military veterans of deployment to Iraq or Afghanistan. Because we're interested in chronic NED, one group consists of veterans who sustained blast-induced MTBIs more than a year prior to study enrolment. This is the B or blast group. The second control group shared similar experiences of deployment, did not sustain a blast-related concussion, the NB group or non-blast group. Women were not included in the study because of the scarcity of women veterans who 8

9 sustained a blast-related concussion precluded recruitment. We screened for hormone deficiencies indicative of any lead to determine its prevalence and the frequency of each type of hormone abnormality in each of the two groups. After identifying individuals who screened positive for NED, they further divide the B and NB groups into those with and without NED. Our abbreviations maybe confusing at first but B always stands for blast-related MTBI and HP for hypopituitarism which is equivalent to NED. N always means no or none. This is the TBI group with NED, the TBI group without hypopituitarism or NED, the non-blast group with NED or hypopituitarism and the non-blast non-hb groups. Questionnaires in neuropsychological test are used to measure the severity and frequency of symptoms and maybe associated with blast-related concussions and/or hormone deficiencies. All veterans who screened positive for hormone deficiencies are offered referral to a VA endocrinologist for clinical evaluation and potential treatment. This is a direct benefit of study participation. Results of the study today shown in the following slides were recently presented at the Society for Behavioral Neuroendocrinology Annual Meeting by Jackie Schultz, the research coordinator of the project. At this point in the study, 13 out of 41 or 31.7% of veterans with blast-induced MTBI are screened positive for one or more hormonal abnormalities characteristic with chronic NED. Only 6.7% of deployed veterans without blast exposure were identified with NED. Growth hormone deficiency has been observed most frequently occurring in 10 of 15 veterans with NED. Four participants screened positive for adrenal insufficiency. I should point out here that our study focuses specifically on blast-related concussions. We expect that many of our participants in both study groups have had concussions from non-blast related incidents at some time in their lives whether or not they identify them as concussions at the time. For this reason, participants with a history of non-blast related MTBI are eligible for an inclusion in our deployment control group. The distinction between the two groups is based solely on the presence or absence of blast-related MTBI. This is a graphic representation of the percentage of each type of hormonal abnormality in each of the participant groups. In the blast or MTBI group shown on the lab, most frequent disorder found was growth hormone deficiency in orange and secondary adrenal insufficiency was next most common in gold. One participant identified by the light blue slice of pie screened positive for both growth hormone deficiency and hypogonadism. One individual screened positive for hypoprolactinemia. In the non-blast or deployment control group, one person screened positive for THD and one for adrenal insufficiency. Each of the succeeding five slides illustrate scores on a specific type of symptom self-report scale. Scores are shown for three of the four subgroups that were formed by subdividing the B and NB groups in the basis of presence or absence of NED. The non-blast group with NED or NB-HP subgroup consisted only of two participants as you saw in the previous slide. It is not included in the graphs, I'll go back to that. These two individuals here in the non-blast group who had 9

10 hormone deficiencies, because they're only two of them were excluded from the remainder of the slides. Dr. Wilkinson: In this group that includes these four small slices of the pie, this is the blast group with hypopituitarism, 13 individuals were in that group and the two groups of normal subjects, there are 28 participants in each group. This group is blast NHP, non-hypopituitarism. This group is non-blast, non-hypopituitarism. Here are the mean and standard deviation scores of each of the three participant subgroups, one more time. On each item, neurobehavioral symptom inventory, 22 items self-report measure of symptoms commonly associated with postconcussion syndrome that may emerge after MTBI. It's one of two core measures selected for concussion healthcare outcomes in the military health system. On every item, the mean score for the blast hypopituitarism subgroup in red is numerically higher than that for the blast MT subgroup and that would neither blast MTBI nor NED. The range of the scale for each item is from zero to five. Because the study is still in progress, detail statistical analysis has not been performed. Again, this is the MTBI NED group which on every one of the items has a higher score and higher score is again indicate more severe or more frequent symptoms. This is the Pittsburgh Sleep Quality Index, it's a self-reported questionnaire that asses the seven aspects of sleep quality over one month time interval. The range of the scale for each item is from zero to three. Once again, the BHP group, the MTBI NED group exhibits higher mean scores on either of the other two groups on all seven of the aspects of sleep disorders. This slide indicate results from the analysis of the PTSD checklist military version, the standardized self-report rating scale for PTSD comprising 17 items that correspond to key PTSD symptoms. The PCL military version is designed to be specific for PTSD caused by military experiences. On this scale, the B-HP subgroup numerically highest mean of the three groups on all but one item and this is trauma remembering significant military experiences. The range of the scale for each item, this measure is from one to five. The patient's health questionnaire for depression is a nine question instrument for screening for the presence and severity of depression. Score is ranged from zero to three. Once again, blast-related MTBI group with NED has been numerically highest mean scores of the three subgroups on each of nine items. Just to refresh your memory a little, this is the group with MTBI but without NED and this is a group with no TBI, no pituitary deficiency. The quality of life assessment of growth hormone deficiency in adults is a disease specific self-report measure of the effect of growth hormone deficiency on patients. It's also been used in other patient populations and has been judged to have good psychometric properties when administered in the general population. The questionnaire consists of 25 yes or no items, scored as one or zero. The higher the score, the poorer the quality of life. The color coding has been altered in this slide with the gray bars now representing to be HP group. 10

11 The mean score of the B-HP group, again the gray bars, is highest or tied for highest on all the two items. One of those is now I will try to find it. I feel as if I let people down right here. The other is I avoid responsibilities if possible. All of the other 25 items, the highest score is in the blast hypopituitarism group. It's clear from inspection of these five figures that in multiple cases, the differences among the score is the three subgroups are not significant. It is compelling that on 86 of the 89 items on the scales combined, the blast hypopituitarism group or TBI-NED group exhibited the highest scores. This is a complex slide so I'll go through it slowly relating the presence of PTSD in each of the groups and indications on each of the different scales. The slide shows the means of the total scores as opposed to the single item scores which represented in the previous slides. In each of five scales that I've discussed plus the nine item fatigue severity scale, each of the three now familiar participant groups is represented but they're subdivided. Again, based on the presence or absence of a clinical diagnosis of PTSD on a clinician administered PTSD scale or CAPS. The bars in shades of orange indicate the mean scores of the participants in each subgroup who are diagnosed with PTSD with the darker shade representing the B-HP group in each case. The bars in shades of blue indicate the mean scores of the participants in each subgroup that did not have a diagnosis of PTSD with the darker shade again representing the B-HP group. In each of the subgroups, the participants with the PTSD diagnosis score higher than those without PTSD. In other words, the orange bars are higher than the blue for all three subgroups on all three scales. Focusing on the groups without PTSD in blue, the means scores of B-HP participants, the dark blue were highest on each of the six scales. The participants with the diagnosis of PTSD, the orange bars, the mean scores of the B-HP group were highest on four of the six scales. This is not shown on the slide but PTSD diagnosis with CAPS was present in 69.2% of the veterans in the concussion-induced NED group compared to 50% in the TBI group without NED and 21.4% in those without a blast-related concussion or NED. These results suggest either that certain specific factors related to blast MTBI are common components of the etiology of both NED and PTSD or that some of the symptoms that contributed is the diagnosis of PTSD are in fact due to MTBI induced pituitary dysfunction in these individuals. The major findings of our studies to date are the 31.7% of veterans with blastrelated MTBI screened positive for NED compared on the 6.7% of participants without MTBI. The type of NED observes most frequently is growth hormone deficiency and clinically diagnosed PSTD was more prevalent in the participant group with blast-related MTBI and NED than in either of the other subject groups. Participants with MTBI and NED consistently endorse more frequent or severe symptoms on all six, that should be six instead of seven here, six of the neurobehavioral scales administered. In conclusion, there's a high prevalence of chronic NED after blast-related MTBI associated with increase symptoms related to sleep, depression, fatigues, and 11

12 quality of life. These results supports screening for hormone deficiencies after blast-related MTBI when indicated suggestive and persistent symptoms and failure to screen for NED may do inappropriate and ineffective treatment of these symptoms whereas identification and treatment of neuroendocrine disorders can lead to facilitation and recovery and rehabilitation. Dr. Wilkinson: Connecting a clinical study of this nature requires a large multidisciplinary group of smart, sensitive, talented and dedicated individuals who work efficiently together as a team. I gratefully acknowledge everyone on this list to which the name Alvin Matsumoto, MD should be added for their outstanding efforts for making this study possible. These are the key takeaway points: mild traumatic brain injury is the single most common injury of service members and recent conflicts. There's a high prevalence of chronic neuroendocrine dysfunction after chronic traumatic brain injury. Symptoms include cognitive deficits, fatigue, depression, sleep disorders, sexual dysfunction, diminished quality of life and increased cardiovascular mortality and the presence of persistent symptoms screening for NED post-ti can result in directed and effective treatment excuse me, and facilitation of recovery and rehabilitation. I'm going to turn it over Mr. Scott Blair for description of the whoops, materials provided by DCoE, DVBIC. Well, thank you, Dr. Wilkinson. That was a lot of really great information and I want to emphasize how important these clinical support tools will be for everybody. Let me just say that I've seen lots and lots of medical records and folks with NED-related dysfunction of private sector and I've never seen any of the private medical folks put together such an amazing clinical screening tool as what you have here. Dr. Wilkinson was a consultant to the working group for this clinic recommendation chart along with many of the other names he previously gave you. I think that the DOD, DVBIC and the VA ought to be really proud of these because these really are on the cutting edge of screening tools that can be used for this type of syndrome. It's a difficult syndrome for many practitioners to narrow it down. It's just beginning to emerge. What this charts will really do is help the clinician with a nice framework of screening tools to look at it to make sense of all of it. I will say that when I've seen folks such as veterans or private citizens get help they need through GH, growth hormone supplementation. It makes an amazing difference in their quality of life. Folks get their life back. They're incredibly thankful to the medical practitioner who's helped them out with this new area and it's really nice to have these so that you can all kind of be ahead of the curve so to speak. I would really encourage everybody who's participating to access these training tools, put them to use within your clinical setting. I think you'll find and really raises the awareness for this and significantly helps the quality of life of the veterans that they'll be treating. I want to give a hearty thank you to Dr. Wilkinson. 12

13 It's now time to answer questions from the audience. If you've now already done so, you may submit questions now via the question pod located on the screen and we'll be happy to respond to as many questions as the time permits. Now, if we're not able to get to your question, you're welcome to contact Dr. Wilkinson and have your question answered as well. We'll now turn to the question section and let's click on this one here. Question, did the study exclude veterans with preexisting or genetic predispositions to endocrine related disorders, i.e. diabetes, Dr. Wilkinson? Dr. Wilkinson: There's not a real short answer to that question but we did exclude individuals with insulin-dependent diabetes because of the potential danger with the glucagon stimulation test that we used. Because we wanted to make this a real world study, we had very few conditions that we excluded. A very few drugs were excluded and preexisting conditions were not excluded except for severe chronic medical conditions or things such as schizophrenia, bipolar disorder, psychosis. We wanted to make it a real world, most of the veterans we worked with, I'm sure most of the veterans that any people in the VA I work with got multiple health problems. If they have a preexisting endocrine problem such as hypogonadism, we did take that into account when we're measuring testosterone, LH and FSH. We excluded few people as long as they met the requirements of the blast exposure and deployment, et cetera. I hope that answers the question. We have another question. It goes as follows, is there a correlation between the age and severity of pituitary dysfunction, i.e. the younger the service members who experienced the blast, the worst the pituitary dysfunction is? Dr. Wilkinson: We don't have a definite answer to that yet. We're still conducting the study and it's not clear. There's no obvious connection and a preliminary study that we conducted earlier, there was no connection. We have looked at the number of blast exposures of individuals and whether or not that was a determining factor in whether or not NED occurred. We found that it was not a factor. Some of these veterans have had it's hard to believe but close to a hundred blast confessions. We have not found any kind of direct relationship between the number of concussions and the prevalence of pituitary dysfunction. Thank you doctor. Another question, have medications used to treat diabetes or depression been tested to see if they assist in managing some of the hyperprolactinemia sometimes since they've mirrored those symptoms? Dr. Wilkinson: This is a question I can't really answer. I am not a clinician. I'm a neuroendocrine researcher. As mentioned before, everyone who does screen positive on any of our test is referred directly to an endocrine specialist here at the VA for clinical evaluation and treatment. Part of me answering the question is, the study is only been going on, now deliberate four years so it's hard to really answer whether or not treatment is effective in any cases. The individuals are being treated though. 13

14 All right, thank you doctor. Another question, have the findings from pituitary gland research resulted in any increase in other medical or mental health research? Dr. Wilkinson: I'm not sure I can answer that at all. One thing I will say is that it's been a very slow process to educate the medical community in general about this problem. As I said, it's a new area. The first perspective study was done in year 2000 but know that it is gradually increasing. The DOD and the VA are definitely where it was and as Mr. Blair said, I think the military and VA system are responding much better to listen to the general medical population. I would add to that private sector, there's still a lot of communication has to take place between the neurological community and many of the other in the endocrine community that's happening but it's coming together a little slower than one might like. Next question. Was there any concern regarding over reporting symptoms on the questionnaire as used in the study because of the participants are being asked the same questions over and over again, i.e. are you difficulty concentrating sleeping, trouble with irritability? Dr. Wilkinson: There is some concern about that. I guess all I can say about that right now is that if the I'm not a neuropsychologist but we do have a neuropsychologist as one of the co-investigators of the project. I have to admit that I depend on her for the validity and the correct interpretation of what we're doing. All right, another question. What is the percentage and/or number of blast E subjects that had hypogonadism? Dr. Wilkinson: I will have to look back at the slide but I believe it was 19%. Okay. Another question, how did you Dr. Wilkinson: That's not correct. Oops. Dr. Wilkinson: If I could go back to I'm going quickly go back to my personal version of the I want to give you a good answer in that if I can quickly. That's not going to work. It was definitely the second in frequency, maybe by the end of the well, this is not going to work either. I'm sorry but if you want to write to me, I'll give you the specific information. Okay. How did you screen for growth hormone deficiency and adrenal insufficiency? Dr. Wilkinson: Good question. For growth hormone deficiency, we used the glucagon stimulation test. That's not accepted by most people in the growth hormone field, can be a very valid measure for growth hormone deficiency. We also used it for our and this again, it's just for screening purposes, not for diagnosis. We also use that in screening for adrenal insufficiency. We measure both ACTH and cortisone in response to the glucagon and I know that when Dr. Garcia who's our 14

15 endocrinologist, when we consult, what he follows up, he uses the syntropin of ACTH stimulation test to confirm the diagnosis of adrenal insufficiency. For our screening, we rely on the GST for both of those. All right, thanks, Doctor. Another question. What can patients do to be proactive about seeking health care for a suspected NED? Dr. Wilkinson: I assume you mean patients in the military or VA system. I'm not certain how to answer that except to provide whatever information they can find about this order through their physician, their PCP or to ask directly for a referral through an endocrinologist. Here's a question, can we have a copy of the PowerPoint? Dr. Wilkinson: I believe it's available directly from DCoE. I'm quite certain it is. Matter of fact, it's already available because a link to it is provided in the announcement of this presentation. That's great so go get that link and there it is. All right, another question. What are the recommendations about collaborative treatment approaches from endocrinologists and mental health providers to address these increased behavioral symptoms in this population of veterans? Dr. Wilkinson: I think that's a fantastic idea. I think that's exactly what should be done. Again, the word is spreading solely about this. It's an area that involves disciplines of endocrinology obviously, psychiatry, neurology. From my standpoint, again as a researcher not as a clinician, but I think there should be much more collaboration. All right, another question, do you have neuropsychological data available and if so, what change do you expect to see with appropriate hormonal replacement therapy? Dr. Wilkinson: We have neuropsychological data available. I didn't present any of the cognitive, purely cognitive data in this presentation. Actually, they haven't been analyzed yet. I would expect to see, and it's been demonstrated with growth hormone replacement for one, improvement in cognitive function in some areas, at least. Again, it's too early to say what is going to happen in these particular subjects but I would expect improved cognitive function. Anecdotally, the folks I've been dealing with who've had hormone replacement therapy have reported significant increases in less social isolation. They feel much more outgoing, much more confident and energetic so it does have impact. Another question, can we refer soldiers for the study or is it completed? Dr. Wilkinson: It's not completed and we definitely welcome volunteers for this study and there is compensation as well as the chance to get a clinical referral. However, you 15

16 said soldiers and for VA studies we're not allowed to recruit active duty personnel. Only veterans are eligible for this study so you're including veterans and soldiers, yes, we'd love to have them. All right, next question, did any of the veterans assessed have baseline cognitive endocrine assessments done prior to combat? Dr. Wilkinson: Not that are available to us, no. Other question, did any of those screens have symptoms of posterior pituitary dysfunction? Dr. Wilkinson: Yes, we definitely have had at least two people that have screen positive for diabetes insipidus, very low levels of vasopressin and have osmolality and sodium, et cetera, levels in urine and plasma to verify the vasopressin levels. We also found one individual with extremely low oxytocin level. This is a followup question to ask the one asked just a couple ago about did any of the veterans assessed have baseline cognitive endocrine assessments done prior to combat, and the followup was and were the findings substantially different? Dr. Wilkinson: Again, I can't answer that. We just don't have those available. I know that there is a screening that goes on when individuals are deployed. They're screening before and after deployment but we don't have access to those records. Here's a question. Law enforcement officers frequently suffer from MTBI secondary to cranial impact that they have some subjects who strike them in the head inducing whiplash, cranial rotation, et cetera. Are there data indicating the prevalence of NED in such individuals? Dr. Wilkinson: I believe there is one study addressing law enforcement personnel. There're several studies now addressing sports concussions. One of the most I guess depressing in a way is there were a couple of studies from Turkey. There's a very good group in Turkey and they looked at boxers and kick-boxers. If you'd only imagine how many times they've been hit in the head and they definitely have a high prevalence of NED. If you like to write to me I can try to find the paper about law enforcement officers. I would just note anecdotally, many of the endocrinologists I've worked with at the private medical sector talk about frequently women who have been abused, for example, hit in the head, will often times have NED, certainly football players, other folks who've had head contact. One of the more prevalent causes are motor vehicle crashes where there's a lot of whiplash and the literature does back that up certainly in the study of Dr. Wilkinson have just referred to. Okay, going on to the next question. How do you screen for growth hormone deficiency and adrenal insufficiency? 16

17 Dr. Wilkinson: We already addressed that one. Okay. Let's move on to this one then. With a low-dose stimulation test or the standard stimulation test used to diagnose deficiency, and is there a current recommendation for which test to use? Dr. Wilkinson: That's a source of some disagreement. I believe that Dr. Garcia uses the low dose. My sense from the literature is that that's generally the favored test to use. Again, I'm answering this not as a clinician but as a researcher and my sense again from the literatures is that it just makes more intuitive sense to me to use the low-dose stimulation test. The high dose is so high, it's so far from physiological. That's just my sense. All right, thank you, doctor. Here's a question. What referrals, specialty or otherwise, should a veteran's VA primary care provider make once she or he is diagnosed with MTBI? Would choice and referrals change if the event that caused the MTBI was 10 years ago? Dr. Wilkinson: I'll answer the second question first. As long as the MTBI that's in question occurred more than a year ago, essentially nothing is likely to have changed. Ten years would not be any significantly different from one year, probably. In either case, I think the individual should be referred to an endocrinologist definitely. The only issue at present is the relative lack of general information about this problem and whether or not it's going to be appropriately investigated. I'm not saying anything negative about PCPs and either the VA or anywhere else but it just is a new area and word is spreading slowly. A followup question on that, Doctor. If a person does have an MTBI, would it make sense for them to get the endocrine testing first since the number is 30 to 50% of these TBI victims who have NED. Would it be helpful for them to get that screened before they undergo any neuropsychological testing to rule out any impacts that the NED might have on the neuropsychological test results? Dr. Wilkinson: Again, that's a question that I don't feel very comfortable answering as a nonclinician but all of the symptoms that I have mentioned that are potential symptoms of neuro-endocrine deficiency, they clearly could be due to other causes, the purely neurological CNS damage, so I really wouldn t like to say what should be done first in a given case. That's a clinical decision. That's not something I can answer. Sure. Here's a question. If we want to refer a patient for endocrinology evaluation, for NED, what should we request? Slightly different than the prior one. Dr. Wilkinson: The best thing that I can say about this is to get the information that Mr. Blair described, the training sides and the clinical guidelines that are provided and refer to those or even provide those to an endocrinologist they're going to referring if the person isn't familiar with the problem. I think that sometimes the best way to do it is to introduce someone, introduce the person to the problem. 17